Myeloidproliferative neoplasms (chronic myeloid proliferative diseases) are a class of diseases mainly involving abnormal growth of hemocytes, which is caused by aberrant hematopoietic stem cells. Specifically, diseases such as polycythemia vera, essential thrombocythemia, and idiopathic myelofibrosis are known (see, for example, Van Etten, et al., 2004, Cancer Cell, 6, 547-552). At present, there is no available therapy for myeloidproliferative neoplasms (chronic myeloid proliferative diseases) and thus there is an earnest desire of therapeutic agent for these diseases.
In 2005, an activated mutation of JAK2, a kind of JAK family tyrosine kinases (JAK2 V617F mutation), was reported in a patient suffering from myeloidproliferative neoplasm (chronic myeloid proliferative disease) (see, for example, Robert Kralovics, et al., 2005, New England Journal of Medicine, 352, 1779-1790). In a subsequent study, the activated mutation was confirmed in about 95% of polycythemia vera patients, about 50% of essential thrombocythemia patients, and about 50% of idiopathic myelofibrosis patients (see, for example, Peter J. Campbell, et al., 2006, New England Journal of Medicine, 355, 2452-2466). Further, another activated mutation of JAK2 (JAK2 D620E mutation) was found in a few cases of polycythemia vera patients (see, for example, L. Richeldi, et al., 2006, Leukemia, 20, 2210-2211). Moreover, activated mutations of c-Mpl in a thrombopoietin receptor (MPL W515L mutation and MPL W515K mutation) were found in about 10% of idiopathic myelofibrosis patients in whom JAK2 V617F was negative.
Since JAK2 is located downstream of the intracellular signal transduction pathway of c-Mpl, a compound having a JAK2 tyrosine kinase inhibitory activity is expected to be an active ingredient for therapeutics in treatment of diseases caused not only by JAK2-activated mutation but also by c-Mpl mutation, e.g., myeloidproliferative neoplasms (chronic myeloid proliferative diseases) (see, for example, Yana Pikman, et al., 2006, PLoS Medicine, 3, 1140-1151, and Animesh D, et al., 2006, Blood, 108, 3472-3476).
JAK2-activated mutations have also been found in other than myeloidproliferative neoplasms (chronic myeloid proliferative diseases). For example, it has been reported that a JAK2 V617F mutation is found at a high rate inpatients belonging to a class of myelodysplastic syndrome (RARS-T) (see, for example, MM Ceesay, et al., 2006, Leukemia, 20, 2060-2061). JAK2-activated mutation (JAK2 R683S/G mutation etc.) has also been found in 16 (about 9%) of 187 cases in infantile acute lymphocytic leukemia patients (see, for example, C. Mullighan, et al., 2009, Proceedings of the National Academy of Science U.S.A, 106, 9414-9418), and in about 20% of infantile acute lymphocytic leukemia patients with Down's syndrome (see, for example, A. Gaikwad, et al., 2008, British Journal of Haematology, 144, 930-932).
It has also been reported that the activation of JAK2 tyrosine kinase generated by JAK2 fusion gene is involved in pathological formation. For example, a TEL-JAK2 fusion protein was found in patients of myeloidproliferative neoplasms (acute myeloid proliferative diseases) and of acute myeloid leukemia, and a BCR-JAK2 fusion protein and a PCM1-JAK2 fusion protein were found in patients of chronic myeloid leukemia-like hematic cancer (see, for example, Lyne Valentino, et al., 2006, Biochemical Pharmacology, 71, 713-721 (“Valentino”)). JAK2 signal transduction pathway is involved in the growth of Bcr-Ab1-positive chronic myeloid leukemia cells, suggesting that a compound having a JAK2 tyrosine kinase inhibitory activity will be effective for imatinib-resistant chronic myeloid leukemia (see, for example, Ajoy K. Samanta, et al., 2006, Cancer Research, 66, 6468-6472). In general, the JAK2 signal transduction pathway is one of important pathways in the growth of hematic cancer cell, and thus, a compound having a JAK2 tyrosine kinase inhibitory activity is expected to have a therapeutic effect for a variety of hematic cancers (see, for example, Valentino).
JAK2 tyrosine kinase is also involved in intracellular signal transduction of cytokine receptors or hormone receptors. Interleukin-6 (IL-6) is an inflammatory cytokine which plays an important role in inflammation, immunoresponse and onset of cancers (see, for example, H. Yu, et al., 2009, Nature Reviews Cancer, 9, 798-809, H. Ogura, et al., 2008, Immunity, 29, 628-636, and R. Catlett-Falcone, et al., 1999, Immunity, 10, 105-115), and the IL-6 signal is transduced through JAK2 tyrosine kinase (see, for example, M. Narazaki, et al., 1994, Proceedings of the National Academy of Science U.S.A, 91, 2285-2289). Diseases in which IL-6 is involved include inflammatory diseases (e.g., rheumatoid arthritis, inflammatory bowel disease, osteoporosis, multiple sclerosis), hematic cancers (e.g., multiple myeloma), solid cancer (e.g., prostatic cancer), and angiopathy (e.g., pulmonary hypertension, arteriosclerosis, aneurysm, varicose vein) (see, for example, P. Heinrich, et al., 2003, Biochemical Journal, 374, 1-20, M. Steiner, et al., 2009, Circulation Research, 104, 236-244, and H. Alexander, et al., 2009, Biochemical Pharmacology, 78, 539-552). Further, it is known that JAK2 tyrosine kinase contributes to intracellular signal transduction of prolactin receptors, and the expressed amount of prolactin receptor increases in breast cancer, resulting in acceleration of the proliferation of cancer cells by prolactin (for example, L. Neilson, et al., 2007, Molecular Endocrinology, 21, 2218-2232).
Thus, it is expected that a compound having a JAK2 tyrosine kinase inhibitory activity exhibits a therapeutic effect for a variety of diseases such as inflammatory diseases, hematic cancers, solid cancers, and angiopathy since JAK2 tyrosine kinase is involved in transduction of extracellular stimulation.
JAK3 is a tyrosine kinase which plays an important role in signal transduction of cytokine, and has attracted considerable attention as a target molecule of immunosuppressants since 10 or more years ago. In fact, compounds having a JAK3 tyrosine kinase inhibitory activity have been subjected to clinical trial as therapeutics for organ transplantation and rheumatoid arthritis (see, for example, Paul S. Changelian, et al., 2003, Science, 302, 875-878).